Adaptive Immunity and MHC - Immunology BMS172

• Level 1, Semester 2 module: Foundations of Immunology BMS172.
• Lecture Title: Adaptive immunity and MHC.

Instructor Information

• Contact: Professor Doctor Mohammed Mahmoud El-Naggar.
• Department: Medical Microbiology and Immunology.
• Email: [email protected].
• Mobile: 01126625177.
• Academic hours are on Sundays from 10:00 AM to 12:00 AM.

Learning Outcomes

• Describe types of adaptive immunity.
• Identify functions of antibody isotypes.
• Compare between primary and secondary humoral immune response.
• Identify types of cell-mediated immunity.
• Define MHC, describe MHC classes, structure, distribution, and functions of MHC molecules.

Lecture Outline

• Types of adaptive immunity (humoral and cellular).
• Primary and secondary humoral immune response.
• Types of cell-mediated immunity.
• Major histocompatibility complex.

Case Scenario

• A 65-year-old man with chronic renal failure received a kidney transplant from a blood group-matched friend, post-transplant, the creatinine levels continuously rose.
• He was told he will be subjected to renal dialysis again.
• Consider what is the proper diagnosis and what tests you should concentrate on for the next operation.

Types of Adaptive Immunity

• Humoral (Antibody-Mediated) Immunity.
• Cell-Mediated Immunity.

Humoral Immunity

• Mediated by secreted antibodies.
• Defends against extracellular microbes and microbial toxins.

Functions of Antibody Isotypes

• Neutralization of microbes and microbial toxins
  • Antibodies block microbe binding to cells, preventing infection.
  • Antibodies inhibit microbe spread from infected cells to adjacent cells.
  • Antibodies block toxin binding to cellular receptors, inhibiting pathologic effects.
• Opsonization and phagocytosis
  • IgG antibodies opsonize (coat) microbes.
  • IgG promotes phagocytosis by binding to Fc receptors.
• Antibody-dependent cell-mediated cytotoxicity (ADCC)
  • IgG binds infected cells via Fab regions.
  • IgG binds Fc receptors on NK cells, activating them to kill cells.
  • IgE binds helminthic parasites via Fab regions.
  • IgE binds Fc receptors on eosinophils, activating them to release granule contents that kill parasites.
• Activation of the complement system by IgG and IgM.
• Functions of antibodies at special sites
  • Mucosal immunity: IgA produced by mucosa-associated lymphoid tissues (MALT) in the GIT and RT and is transported into the lumens of organs.
  • IgA binds to and neutralizes microbes and toxins in mucosal secretions, blocking entry.
  • Neonatal immunity: IgG passively provides immunity to neonates.
  • IgG is transported across the placenta into the fetal circulation.
• IgG is received from ingested milk transported across the gut epithelium of newborns.

Primary Response

• A lag of 10 days before specific antibody becomes detectable.
• The antibody is predominantly IgM.
• The antibody level declines after a short time.

Secondary Response

• More rapid appearance of antibody.
• Greater amount of antibody.
• IgG class antibody.
• Antibody remains detectable for months or years.
• Upon re-exposure to a different antigen at the same time as the original, the response to the new antigen will be a primary response.
• The immune system possesses specific immunologic memory for antigens.
• During the primary response, B lymphocytes become long-lived memory cells.
• The secondary response requires class switching (IgM to IgG).

Cell-Mediated Immunity

• Eradicates infections from intracellular microbes.
• Activation of naïve T cells to proliferate and differentiate.
• Effector cells: CD4+ T helper cells and CD8+ cytolytic cells (CTLs) and the elimination of the intracellular microbes.

Types of Cell-Mediated Immunity

• CD4+ T cells differentiate according to cytokine production by antigen presenting cell
  • IL-12 leads to Th1
  • IL-4 leads to Th2
• Th1 cells
  • Secrete IFN-γ.
  • Activates phagocytes to kill microbes.
• Th2 cells
  • Secrete IL-4 and IL-5.
  • Stimulates eosinophil and mast cell degranulation in allergy and helminthic infection.
• CD8+ T cells
  • Kills any cells containing microbes or microbial proteins in the cytoplasm (intracellular).
  • Accomplished by direct cell cytotoxicity
  • Eliminates the reservoir of infection.

Activation of T Cells occurs via Two Signals

• First signal: peptide + MHC on the surface of APCs recognized by TCR-CD3.
• Second co-stimulatory signal: interaction of B7 molecule on APCs with CD28 on T cells.
• The absence of the second signal leads to anergy (unresponsiveness).

Steps of Killing of Infected Cells by CD8+ CTLs

• CTLs recognize class I MHC + peptides on the surface of infected "target cell."
• Formation of tight adhesions “conjugates" with these cells.
• CTLs are activated by IL-2 & IFN-γ to release their granule contents toward the target cell
• The granules contents include
  • Perforin: forms pores in the target cell membrane.
  • Granzymes: enter the target cells through these pores and induce apoptosis via activation of caspases.
• Detachment of CTL from target cells to kill other target cells.
• Death of target cell.

Major Histocompatibility Complex (MHC)

• Group of genes located on the short arm of chromosome 6.
• Produces MHC molecules presented on cell surfaces.
• Responsible for display of protein Ag to T cell.
• Also called human leucocytic Ag (HLA).

Classification of Genes

• Class I MHC genes
  • HLA-A, HLA-B, and HLA-C.
  • Play a role in Ag presentation to Tc.
• Class II MHC genes
  • HLA-D region (HLA-DR, HLA-DP, and HLA-DQ).
  • Play a role in Ag presentation to Th.
• Class III MHC genes
  • Lies between class I & II, and does not produce MHC.
  • Produces some complement components & TNF-α.

Structure and Distribution of MHC Molecules

• Membrane proteins expressed on cells.
• Both class I & II molecules consist of an extracellular, transmembrane, and cytoplasmic part to anchor the molecule to the cell.

Class I MHC Molecules

• Two polypeptide chains: α chain (3 domains: α1, α2, α3), attached to β2 microglobulin (encoded by a gene outside MHC).
• α1 and α2 domains form the cleft or groove which binds peptide.
• Presents antigen to CD8+ cells.
• Expressed on all nucleated cells.

Class II MHC Molecules

• Two polypeptide chains: α chain (α1 & α2) and β chain (β1 & β2).

• α1 and β1 domains form the peptide binding cleft.

• Presents antigen to CD4+ cells.

• Expressed on APCs only.

• Class I MHC present antigen to: Th (CD4), NK, Tc (CD8), Monocytes, Macrophages.

• During activation of T cells, the 2nd co-stimulatory signal is the interaction of: B7 molecule on APCs with CD28 on T cells.

• The primary immune response in antibody formation is characterized by first exposure to antigen, is usually formed of IgM and is slow in onset.